Abstract The nervous system plays a pivotal role in cancer biology, and pathological investigations have consistently linked intratumoral nerve density to cancer aggressiveness and metastasis. However, the precise impact of cancer-associated neurons on cancer cell biology and the communication channels established at the interface between nerves and cancer remain poorly known. We show that cancer-associated neurons contribute to cancer metabolic plasticity through the transfer of mitochondria from nerves to cancer cells. Breast cancer denervation and nerve-cancer coculture models confirmed the role of cancer-associated neurons in improving tumor energetics in the breast cancer context. Neurons stimulated by cancer cells in coculture undergo metabolic reprogramming, exhibiting a significant increase in mitochondrial mass coupled with the transfer of their mitochondria into neighboring cancer cells. To precisely track the fate of recipient cancer cells, we developed MitoTRACER, a novel genetic reporter of the cell-cell transfers of mitochondria that permanently mark recipient cells and their progeny. Lineage tracing and fate mapping of cancer cells having acquired mitochondria from neuronal donors in the primary tumor revealed their selective enrichment at metastatic sites following cancer dissemination. Collectively, our data highlight the enhanced capacities of cells that receive mitochondria from neurons in the primary tumor to successfully form distant metastases, shedding light on how the nervous system supports cancer metabolism and metastatic dissemination. Citation Format: Gregory Hoover, Shila Gilbert, Olivia Curley, Clémence Obellianne, Mike T. Lin, William Hixson, Terry W. Pierce, Joel F. Andrews, Mikhail F. Alexeyev, Fariba Behbod, Daniel Medina, Jeffrey T. Chang, Gustavo Ayala, Simon Grelet. Lineage tracing of the intercellular transfer of mitochondria during cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr SY23-01.

The nervous system has a pivotal role in cancer biology, and pathological investigations have linked intratumoural nerve density to metastasis1. However, the precise impact of cancer-associated neurons and the communication channels at the nerve-cancer interface remain poorly understood. Previous cancer denervation models in rodents and humans have highlighted robust cancer dependency on nerves, but the underlying mechanisms that drive nerve-mediated cancer aggressivity remain unknown2,3. Here we show that cancer-associated neurons enhance cancer metabolic plasticity by transferring mitochondria to cancer cells. Breast cancer denervation and nerve-cancer coculture models confirmed that neurons significantly improve tumour energetics. Neurons cocultured with cancer cells undergo metabolic reprogramming, resulting in increased mitochondrial mass and subsequent transfer of mitochondria to adjacent cancer cells. To precisely track the fate of recipient cells, we developed MitoTRACER, a reporter of cell-to-cell mitochondrial transfer that permanently labels recipient cancer cells and their progeny. Lineage tracing and fate mapping of cancer cells acquiring neuronal mitochondria in primary tumours revealed their selective enrichment at metastatic sites following dissemination. Collectively, our data highlight the enhanced metastatic capabilities of cancer cells that receive mitochondria from neurons in primary tumours, shedding new light on how the nervous system supports cancer metabolism and metastatic dissemination.

Habitat fragmentation can negatively impact wildlife populations by simplification of ecological interactions, but little is known about how these impacts extend to host-associated symbiotic communities. The symbiotic communities of amphibians play important roles in anti-pathogen defences, particularly against the amphibian chytrid fungus Batrachochytrium dendrobatidis (Bd). In this study, we analyse the role of macroparasitic helminth communities in concert with microbial communities in defending the host against Bd infection within the context of forest fragmentation. We found that skin microbial and helminth communities are disrupted at fragmented habitats, while gut microbiomes appear more resilient to environmental change. We also detected potential protective roles of helminth diversity and anti-pathogen microbial function in limiting Bd infection. Microbial network analysis revealed strong patterns of structure in both skin and gut communities, with helminths playing central roles in these networks. We reveal consistent roles of microbial and helminth diversity in driving host–pathogen interactions and the potential implications of fragmentation on host fitness.

We previously reported on high expression of define PDCD2 in human malignancies. Knockdown of PDCD2 reduced the proliferation of leukemia and lung carcinoma cells. However, the mechanism by which PDCD2 reduces tumor proliferation remains unclear. This study tested the hypothesis that lowered PDCD2 would delay the proliferation of A549 lung carcinoma cells. Entry of A549 cells into S-phase was significantly (p-value 0.05) delayed when PDCD2 was knockdown. This correlated with a significant downregulation of cyclin D1, and AKT phosphorylation. Inhibition of the PI3K/AKT signaling pathway by Ly294002 decreased levels of PDCD2. These findings are consistent with a role for PDCD2 to mediate the entry of A549 cells into the cell cycle. Resting A549 cells showed PDCD2 localizing in the nucleus and plasma membrane and became diffuse with cell division, suggesting that PDCD2 is mitogen-dependent and may be involved in the proper timing of cell cycle. These findings may represent a promising venue to develop PDCD2 in clinical applications.

Antimicrobial resistance has been stated to be a global health problem. In Chile, the use of antibiotics should be declared by medical prescription, but it is unknown what happens to the drugs once the treatment ends. Among the possibilities for their disposal are the trash or the drain; regardless of which scenario arises, antibiotics could accumulate in the environment, stimulating the emergence of antimicrobial resistance mechanisms and their transfer between microorganisms. Unfortunately, sometimes wastewater ends up in bodies of water, due to the dragging of elements by rain, or by the presence of illegal water discharges. In this work, shotgun metagenomics was used to elucidate the functional and microbial composition of biohazard elements in the bay of Puerto Varas City, Chile. As expected, a high diversity of microorganisms was found, including bacterial elements described as human or animal pathogens. Also, a diverse repertory of antimicrobial resistant genes (ARGs) was detected, which confers mainly resistance to macrolides, beta-lactams, and tetracyclines, consistent with the families of antibiotics most used in Chile. Similar ARGs were identified in DNA mobile elements. In addition, we tested the antimicrobial susceptibility in 14 bacterial strains isolated from Llanquihue Lake. This is the first report of the presence of genomic elements that could constitute a health problem, considering the importance of the interconnection between environmental, animal, and human health, a concept known as One Health.

Water bodies constitute natural, social, and ecological heritage under constant threat from the footprint of human action. They are the habitats of many species and play a key role in sustaining biodiversity in different ecosystems. However, anthropogenic activity can result in eutrophication of water bodies, favoring the excessive growth of microorganisms, which can be a risk factor for animal, human, and environmental health. The Agricultural and Livestock Service [Servicio Agrícola y Ganadero, (SAG)] of Chile developed a list of Mandatory Reportable Diseases (MRD) to report suspected contagious diseases of veterinary relevance. In this sense, the detection of microorganisms in water bodies for the characterization of their sanitary status is important for the development of monitoring strategies and the prevention of possible diseases. This study aimed to determine the presence of potentially harmful bacteria in Llanquihue urban wetlands. Here, we used metagenomic sequencing of amplicons to characterize the composition of microorganisms in three urban wetlands in the city of Llanquihue, which could be a risk factor for animal health. Our main finding was the detection of genera that may be associated with MRD, in addition to other microbial genera that have pathogenic potential. On the other hand, we also report the presence of cyanobacteria genera that can be involved in toxin production in water bodies as another potential source of risk. This is the first study to use massive sequencing techniques to analyze the sanitary status of urban wetlands in the city of Llanquihue.

It has become increasingly clear in the last few years that gene expression in eukaryotes is not a linear process from mRNA synthesis in the nucleus to translation and degradation in the cytoplasm, but works as a circular one where the mRNA level is controlled by crosstalk between nuclear transcription and cytoplasmic decay pathways. One of the consequences of this crosstalk is the approximately constant level of mRNA. This is called mRNA buffering and happens when transcription and mRNA degradation act at compensatory rates. However, if transcription and mRNA degradation act additively, enhanced gene expression regulation occurs. In this work, we analyzed new and previously published genomic datasets obtained for several yeast mutants related to either transcription or mRNA decay that are not known to play any role in the other process. We show that some, which were presumed only transcription factors (Sfp1) or only decay factors (Puf3, Upf2/3), may represent examples of RNA-binding proteins (RBPs) that make specific crosstalk to enhance the control of the mRNA levels of their target genes by combining additive effects on transcription and mRNA stability. These results were mathematically modeled to see the effects of RBPs when they have positive or negative effects on mRNA synthesis and decay rates. We found that RBPs can be an efficient way to buffer or enhance gene expression responses depending on their respective effects on transcription and mRNA stability.

AbstractGenetically engineered mouse mammary cancer models have been used over the years as systems to study human breast cancer. However, much controversy exists on the utility of such models as valid equivalents to the human cancer condition. To perform an interspecies gene expression comparative study in breast cancer we used a mouse model that most closely resembles human breast carcinogenesis. This system relies on the transplant of p53 null mouse mammary epithelial cells into the cleared mammary fat pads of syngeneic hosts. Serial analysis of gene expression (SAGE) was used to obtain gene expression profiles of normal and tumor samples from this mouse mammary cancer model (>300,000 mouse mammary-specific tags). The resulting mouse data were compared with 25 of our human breast cancer SAGE libraries (>2.5 million human breast-specific tags). We observed significant similarities in the deregulation of specific genes and gene families when comparing mouse with human breast cancer SAGE data. A total of 72 transcripts were identified as commonly deregulated in both species. We observed a systematic and significant down-regulation in all of the tumors from both species of various cytokines, including CXCL1 (GRO1), LIF, interleukin 6, and CCL2. All of the mouse and most human mammary tumors also displayed decreased expression of genes known to inhibit cell proliferation, including NFKBIA (IKBα), GADD45B, and CDKN1A (p21); transcription-related genes such as CEBP, JUN, JUNB, and ELF1; and apoptosis-related transcripts such as IER3 and GADD34/PPP1R15A. Examples of overexpressed transcripts in tumors from both species include proliferation-related genes such as CCND1, CKS1B, and STMN1 (oncoprotein 18); and genes related to other functions such as SEPW1, SDFR1, DNCI2, and SP110. Importantly, abnormal expression of several of these genes has not been associated previously with breast cancer. The consistency of these observations was validated in independent mouse and human mammary cancer sets.This is the first interspecies comparison of mammary cancer gene expression profiles. The comparative analysis of mouse and human SAGE mammary cancer data validates this p53 null mouse tumor model as a useful system closely resembling human breast cancer development and progression. More importantly, these studies are allowing us to identify relevant biomarkers of potential use in human studies while leading to a better understanding of specific mechanisms of human breast carcinogenesis.

PDF file - 1165K, Characterization of 14-3-3zeta Transgenic Mice and Mammary Tumors (S1); Analysis of Metastasis in Mammary Tumors (S2); Apoptosis Assays in Transgenic Mice and Cell Lines (S3); IHe Staining of Ki-67 and p21 Expression (S4); p27-Targeting miRNA Expression in Human Breast Cancer Cell Lines (S5); Analysis of Signaling Pathways Involved in 14-3-3zeta-Mediated miR-221 Transcriptional Upregulation (S6); Logistic regression model (S7).

Background CAPRA (NCT02565992) evaluated Coxsackievirus A21 (V937) + pembrolizumab for metastatic/unresectable stage IIIB–IV melanoma. Methods Patients received intratumoral V937 on days 1, 3, 5, and 8 (then every 3 weeks [Q3W]) and intravenous pembrolizumab 2 mg/kg Q3W from day 8. Primary endpoint was safety. Results Median time from first dose to data cutoff was 32.0 months. No dose-limiting toxicities occurred; 14% (5/36) of patients experienced grade 3‒5 treatment-related adverse events. Objective response rate was 47% (complete response, 22%). Among 17 responders, 14 (82%) had responses ≥ 6 months. Among 8 patients previously treated with immunotherapy, 3 responded (1 complete, 2 partial). Responses were associated with increased serum CXCL10 and CCL22, suggesting viral replication contributes to antitumor immunity. For responders versus nonresponders, there was no difference in baseline tumor PD-L1 expression, ICAM1 expression, or CD3 + infiltrates. Surprisingly, the baseline cell density of CD3 + CD8 − T cells in the tumor microenvironment was significantly lower in responders compared with nonresponders ( P = 0.0179). Conclusions These findings suggest responses to this combination may be seen even in patients without a typical “immune-active” microenvironment. Trial registration number NCT02565992.

Supplementary Table 2 from From Mice to Humans

Supplementary Methods from Identification of an Integrated SV40 T/t-Antigen Cancer Signature in Aggressive Human Breast, Prostate, and Lung Carcinomas with Poor Prognosis

Supplementary data Figure S1. Functional role(s) of BMI-1 in PCa. Figure S2. BMI-1 expression in subpopulations of DU145 cells. Figure S3. Pharmacological inhibition of BMI-1. Figure S4. Molecular and cellular effects of pharmacological targeting of BMI-1. Figure S5. Examining BMI-1 inhibitors in toxicological assays and effects on normal cells. Figure S6. Toxicity effects of C-209 and CHX on adult and embryo zebrafish. Figure S7. BMI-1 inhibition effect on the normal prostate and hematopoietic system. Figure S8. Representative images of BMI-1 expression in primary PCa samples. Figure S9. Xenografts of human primary PCa cells in embryonic zebrafish. Figure S10. Xenografts of primary PCa tissue in zebrafish embryos. Figure S11. Toxicology assays of chemotherapy and BMI-1 inhibitors in embryonic zebrafish. Figure S12. Anti-tumor activity of BMI-1 inhibitors. Figure S13. Representative H&E staining of mouse xenograft sections indicating the histological effects of treatments. Figure S14. In vivo pharmacological targeting of BMI-1 in androgen independent DU145 and androgen sensitive 22rv1 PCa mouse xenografts. Figure S15. Colony-formation frequency evaluated by dilution analysis of xenograft-derived cells from untreated mice and mice treated with C-209 60mg/kg/day. Figure S16. BMI-1 inhibition effects on androgen-dependent and -independent cells.

Supplementary Figure 7 from Identification of Tumor-Initiating Cells in a p53-Null Mouse Model of Breast Cancer

Supplementary Table 3 from From Mice to Humans

Supplementary Data from Carcinoma-Associated Fibroblast–Like Differentiation of Human Mesenchymal Stem Cells

PDF file - 297K, Tumor incidence and latency in MMTV-HA-14-3-3zeta transgenic and wild type mice (S1); Mammary tumor histology and latency in female MMTV-HA-14-3-3zeta transgenic mice (S2); TMA Analysis (S3); Confusion matrix of SVM (S4).

Supplementary Methods, Tables 1-4, Figure Legends 1-9 from Identification of Tumor-Initiating Cells in a p53-Null Mouse Model of Breast Cancer

Supplementary Table 4 from Identification of an Integrated SV40 T/t-Antigen Cancer Signature in Aggressive Human Breast, Prostate, and Lung Carcinomas with Poor Prognosis